Simplex autism (a subset of the disorder that has been greatly expanded and recently named the “autism spectrum disorder”, ASD) is a multifactorial trait––not that different from many human complex diseases, as well as such phenotypes as drug efficacy and dose-independent adverse drug reactions. Multifactorial traits are the result of contributions from hundreds or thousands of genes, epigenetic effects, and environmental insults as a function of time.

Authors [attached] performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For most of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variants (SNVs) had been detected by microarray or whole-exome sequencing (WES). Authors integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. They found that, compared to control individuals, probands showed a significant (P =0.03) enrichment of de novo and private disruptive mutations within fetal central nervous system DNase I hypersensitive sites (i.e. putative regulatory regions). This effect was observed only within 50 kb of genes that had been previously associated with autism risk, including genes in which sensitivity had already been established by recurrent disruptive de novo protein-coding mutations. These genes included ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM.

In addition, authors provided evidence of gene-disruptive CNVs (in the DISC1, WNT7A, RBFOX1, and MBD5 genes), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes such as CANX, SAE1, and PIK3CA. These data results suggest that detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.

For anyone who wishes to know more about any of these genes––their proper names and functions––one can find all this information (and more) at http://www.genenames.org/, a web site that every geneticist and genetics-oriented scientist should bookmark and use frequently.